Rashid Farooq, Suleman Muhammad, Shah Abdullah, Dzakah Emmanuel Enoch, Wang Haiying, Chen Shuyi, Tang Shixing
Dermatology Hospital, Southern Medical University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
Front Microbiol. 2021 Jul 16;12:703145. doi: 10.3389/fmicb.2021.703145. eCollection 2021.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been continuously mutating since its first emergence in early 2020. These alterations have led this virus to gain significant difference in infectivity, pathogenicity, and host immune evasion. We previously found that the open-reading frame 8 (ORF8) of SARS-CoV-2 can inhibit interferon production by decreasing the nuclear translocation of interferon regulatory factor 3 (IRF3). Since several mutations in ORF8 have been observed, therefore, in the present study, we adapted structural and biophysical analysis approaches to explore the impact of various mutations of ORF8, such as S24L, L84S, V62L, and W45L, the recently circulating mutant in Pakistan, on its ability to bind IRF3 and to evade the host immune system. We found that mutations in ORF8 could affect the binding efficiency with IRF3 based on molecular docking analysis, which was further supported by molecular dynamics simulations. Among all the reported mutations, W45L was found to bind most stringently to IRF3. Our analysis revealed that mutations in ORF8 may help the virus evade the immune system by changing its binding affinity with IRF3.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）自2020年初首次出现以来一直在不断变异。这些变化导致该病毒在传染性、致病性和宿主免疫逃逸方面产生了显著差异。我们之前发现，SARS-CoV-2的开放阅读框8（ORF8）可通过降低干扰素调节因子3（IRF3）的核转位来抑制干扰素的产生。由于已观察到ORF8中的几个突变，因此，在本研究中，我们采用结构和生物物理分析方法来探索ORF8的各种突变，如S24L、L84S、V62L和巴基斯坦最近流行的突变体W45L，对其结合IRF3和逃避宿主免疫系统能力的影响。我们发现，基于分子对接分析，ORF8中的突变会影响与IRF3的结合效率，分子动力学模拟进一步支持了这一点。在所有报道的突变中，发现W45L与IRF3的结合最紧密。我们的分析表明，ORF8中的突变可能通过改变其与IRF3的结合亲和力来帮助病毒逃避免疫系统。
